Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Basic toxicokinetic assessment according to ECHA Guidance on information requirments R7.c
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
other: ECHA Guidance r7.c
Deviations:
not applicable
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-[(1-amino-9,10-dihydro-4-hydroxy-9,10-dioxo-2-anthryl)oxy]ethyl ethyl carbonate
EC Number:
254-959-7
EC Name:
2-[(1-amino-9,10-dihydro-4-hydroxy-9,10-dioxo-2-anthryl)oxy]ethyl ethyl carbonate
Cas Number:
40530-60-7
Molecular formula:
C19H17NO7
IUPAC Name:
2-[(1-amino-9,10-dihydro-4-hydroxy-9,10-dioxo-2-anthryl)oxy]ethyl ethyl carbonate

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral/gastrointestinal absorption:
Owing to the molecular weight (371.3 g/mol) and poor solubility in water (0.224 µg/L) of Disperse Red 302, it can be concluded that the substance may have a limited absorption by means of passage through aqueous pores or be carried through the epithelial barrier by the bulk passage of water in the gastrointestinal tract. However, the substance being lipophilic (log Pow = 6.39) and poorly water soluble (0.224 µg/L), absorption is expected to occur via micellular solubilisation. In an acute oral toxicity study with Disperse Red 302, 3 males and 3 females received a single dose of 2000 mg/kg bw in a stepwise manner. No deaths occurred during the study. No clinical signs were observed in all males during the observation period. One female animal was observed with ruffled fur, hunched posture and tremor from 1 to 5 hours after the administration. Two female animals showed a marked loss of body weight (24.5 and 23 %) one week after treatment. The body weight of the other animals was within the range commonly recorded for animals of this strain and age. No macroscopic findings were observed at necropsy. In the combined repeated dose toxicity study with reproduction/developmental screening with the read-across substance Disperse Red 302:1, three females receiving 300 mg/kg bw/day and three females receiving 1000 mg/kg bw/day showed red staining of the urine during behavioural assessments. At necropsy, red coloured contents within the gastrointestinal tract and urinary bladder were observed in many animals at all doses. One female was found to have red discoloration of mammary gland at 300 mg/kg bw/day. These findings were without any toxicological significance, however are indicative of absorption of the substance taking place along the gastrointestinal tract.

Dermal absorption:
Based on the molecular weight (371.3 g/mol), high partition coefficient (log Pow = 6.39), and poor water solubility (0.224 µg/L at 20 °C), a low dermal penetration rate is expected for Disperse Red 302. The poor water solubility means the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis. Disperse Red 302 was neither corrosive nor irritating to the skin as well as eyes, while, it was not sensitising to the skin. No deaths or systemic toxicity was observed in the local lymph node assay with the Disperse Red 302. The physicochemical properties and evidence from the irritation studies as well as lymph node assay, suggest that Disperse Red 302 may get absorbed to a very limited extent if it is exposed dermally at high doses.

Respiratory absorption:
Disperse Red 302 can be considered to have low volatility based on its low vapour pressure (1.46E-9 Pa at 20 °C), so the potential for the generation of inhalable forms is low. The substance may be taken up by micellular solubilisation owing to it having high partition coefficient (Log Pow = 6.39), and poor water solubility (0.224 µg/L at 20 °C). Therefore, it is possible that the substance will be absorbed to a limited extent if it is inhaled at high doses.
Details on distribution in tissues:
Findings of red stained urine during behavioural assessments and presence of coloured content in urinary bladder during necropsy in the combined repeated dose toxicity study with reproduction/developmental screening with the read-across substance Disperse Red 302:1, point to the substance/metabolites getting transported to the kidneys for excretion via urine. Further, a finding of red discoloration of mammary glands in a female at 300 mg/kg bw/day was also reported in the study, which points to a wider distribution throughout the body via the circulation. The substance being lipophilic in nature, some accumulation in adipose tissue may occur.
Details on excretion:
Route of excretion for Disperse Red 302 has not been investigated. However, owing to the lipophilic nature of the substance and low water solubility, the substance is expected to be predominantly excreted via faeces. However, appearance of the red coloured urine observed in the combined repeated dose toxicity study with reproduction/developmental screening with the read-across substance Disperse Red 302:1, indicates that Disperse Red 302 may also get metabolized to a hydrophilic product and may also be excreted in urine especially at the high doses.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Currently available oral toxicity studies do not provide information about the metabolic cleavage of the substance. However, Disperse Red 302 was found to be mutagenic with Salmonella typhimurium strain TA 1537 in the presence of metabolic activation in the bacterial reverse mutation assay. Further, the read-across substance Disperse Red 302:1 was also found to be clastogenic in the presence of metabolic activation in the in vitro mammalian chromosomal aberration assay. These findings indicate that hepatic metabolism may takes place, however, it should be taken into consideration that rat S9 fraction is not equivalent to the human metabolism. If and to which extent absorbed test material is enzymatically modified or degraded is currently unknown. The appearance of red coloured urine after the oral administration of the substance in the combined repeated dose toxicity study with reproduction/developmental screening with the read-across substance Disperse Red 302:1, indicates that Disperse Red 302 may also undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.

Applicant's summary and conclusion

Conclusions:
Based on the available information, it can be concluded that Disperse Red 302 would be absorbed primarily in the gastrointestinal tract, while very limited absorption via dermal and inhalation exposure can be expected at high doses. Systemic distribution is expected to occur throughout the body. Since the substance is lipophilic in nature, some accumulation in adipose tissue may occur. Predominant route of excretion is expected to be through faeces, however, upon absorption the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine and with the bile at high doses.
Executive summary:

Based on the available information, it can be concluded that Disperse Red 302 would be absorbed primarily in the gastrointestinal tract, while very limited absorptionviadermal and inhalation exposure can be expected at high doses. Systemic distribution is expected to occur throughout the body. Since the substance is lipophilic in nature, some accumulation in adipose tissue may occur. Predominant route of excretion is expected to be through faeces, however, upon absorption the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excretedviaurine and with the bile at high doses.